A number of central nervous system disorders such as anxiety, depression, motor disorders, etc., are believed to involve a disturbance of the neurotransmitter 5-hydroxytryptamine (5-HT) or serotonin. Serotonin is localized in the central and peripheral nervous systems and is known to affect many types of conditions including psychiatric disorders, motor activity, feeding behavior, sexual activity, and neuroendocrine regulation among others. The effects of serotonin are regulated by the various 5-HT receptor subtypes. Known 5-HT receptors include 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 subtypes.
The recently identified human 5-hydroxytryptamine-6 (5-HT6) receptor subtype has been cloned, and the extensive distribution of its mRNA has been reported. Highest levels of 5-HT6 receptor mRNA have been observed in the olfactory tubercle, the striatum, nucleus accumbens, dentate gyrus and CA1, CA2 and CA3 regions of the hippocampus. Northern blots have revealed that 5-HT6 receptor mRNA appears to be exclusively present in the brain, with little evidence for its presence in peripheral tissues.
The high affinity of a number of antipsychotic agents for the 5-HT6 receptor, in addition to its mRNA localization in striatum, olfactory tubercle and nucleus accumbens suggests that some of the clinical actions of these compounds may be mediated through this receptor. Compounds which interact with, stimulate or inhibit the 5-HT6 receptor are commonly referred to as 5-HT6 ligands. These 5-HT6 receptor ligands are believed to be of potential use in the treatment of a variety of central nervous system disorders such as anxiety, depression, epilepsy, obsessive-compulsive disorders, migraine, cognitive disorders, sleep disorders, feeding disorders, panic attacks, disorders relating to withdrawl from drug abuse, schizophrenia, or the like or in the treatment of certain gastrointestinal disorders such as irritable bowel syndrome.
Therefore, it is an object of this invention to provide compounds which are useful as therapeutic agents in the treatment of a variety of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is another object of this invention to provide therapeutic methods and pharmaceutical compositions useful for the treatment of central nervous system disorders related to or affected by the 5-HT6 receptor.
It is a feature of this invention that the compounds provided may also be used to further study and elucidate the 5-HT6 receptor.
These and other objects and features of the invention will become more apparent by the detailed description set forth hereinbelow.
The present invention provides a compound of formula I wherein 
Q is SO2, CO, CONR24, CSNR25 or CH2;
W is N or CR6;
X is N or CR7;
Y is NR8 or CR9R10;
n is 0 or an integer of 1 or 2;
Z is NR11 or CR12R13 with the proviso that when n is 1, Q is SO2 CO or CH2, and W is CR6 then Z must be CR12R13 and with the further provisos that when Y is NR8 then Z must be CR12R13 and at least one of Y and Z must be NR8 or NR11;
R1, R2 and R7 are each independently H, halogen, CN, OCO2HR14, CO2R15, CONR29R30, CNR16NR17R18, SOmR19, NR20R21, OR22, COR23 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R3, R4, R9, R10, R12 and R13 are each independently H or an optionally substituted C1-C6alkyl group;
R5 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
m is 0 or an integer of 1 or 2;
R6 is H, halogen, or an optionally substituted C1-C6alkyl, C1-C6alkoxy, aryl or heteroaryl group;
R8 and R11 are each independently H, CNR26NR27R28 or a C1-C6alkyl, C3-C6cycloalkyl, cycloheteralkyl, aryl or heteroaryl group each optionally substituted;
R14, R15, R22 and R23 are each independently H or an optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;
R16, R17, R18, R20, R20, R26, R27, R28, R29 and R30 are each independently H or C1-C4alkyl;
R19 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
R24 and R25 are each independently H or an optionally substituted C1-C6alkyl, aryl or heteroaryl group; and
---- represents a single bond or a double bond; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
The present invention further provides methods and compositions useful for the treatment of central nervous system disorders affected by or related to the 5-HT6 receptor.
The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recent receptors to be identified by molecular cloning. Its ability to bind a wide range of therapeutic compounds used in psychiatry, coupled with its intriguing distribution in the brain has stimulated significant interest in new compounds which are capable of interacting with or affecting said receptor. At present, there are no known fully selective agonists. Significant efforts are being made to understand the possible role of the 5-HT6 receptor in psychiatry, cognitive dysfunction, motor function and control, memory, mood and the like. To that end, compounds which demonstrate a binding affinity for the 5-HT6 receptor are earnestly sought both as an aid in the study of the 5-HT6 receptor and as potential therapeutic agents in the treatment of central nervous system disorders.
Surprisingly, it has now been found that heterocyclylindazole or -azaindazole compounds of formula I demonstrate affinity for the 5-HT6 receptor along with significant receptor sub-type selectivity. Advantageously, said formula I compounds are effective therapeutic agents for the treatment of central nervous system (CNS) disorders associated with or affected by the 5-HT6 receptor. Accordingly, the present invention provides heterocyclylindazole or -azaindazole compounds of formula I 
wherein
Q is SO2, CO, CONR24, CSNR25 or CH2;
W is N or CR6;
X is N or CR7;
Y is NR8 or CR9R10;
n is 0 or an integer of 1 or 2;
Z is NR11 or CR12R13 with the proviso that when n is 1, Q is SO2, CO or CH2, and W is CR6 then Z must be CR12R13 and with the further provisos that when Y is NR8 then Z must be CR12R13 and at least one of Y and Z must be NR8 or NR11;
R1, R2 and R7 are each independently H, halogen, CN, OCO2R14, CO2R15, CONR29R30, CNR16NR17R18, SOmR19, NR20R21, OR22, COR23 or a C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group each optionally substituted;
R3, R4, R9, R10, R12 and R13 are each independently H or an optionally substituted C1-C6alkyl group;
R5 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
m is 0 or an integer of 1 or 2;
R6 is H, halogen, or an optionally substituted C1-C6alkyl, C1-C6alkoxy, aryl or heteroaryl group;
R8 and R11 are each independently H, CNR26NR27R28 or a C1-C6alkyl, C3-C6cycloalkyl, cycloheteralkyl, aryl or heteroaryl group each optionally substituted;
R14, R15, R22 and R23 are each independently H or an optionally substituted C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C3-C6cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group;
R16, R17, R18, R20, R21, R26, R27, R28, R29, and R30 are each independently H or C1-C4alkyl;
R19 is an optionally substituted C1-C6alkyl, aryl or heteroaryl group;
R24 and R25 are each independently H or an optionally substituted C1-C6alkyl, aryl or heteroaryl group; and
---- represents a single bond or a double bond; or the stereoisomers thereof or the pharmaceutically acceptable salts thereof.
As used in the specification and claims, the term halogen designates Br, Cl, I or F; the term aryl designates phenyl or naphthyl; and the term cycloheteroalkyl designates a 5- to 7-membered monocyclic ring system containing 1 or 2 heteroatoms, which may be the same or different, selected from N, O or S and optionally containing one double bond. Exemplary of the cycloheteroalkyl ring systems included in the term as designated herein are the following rings wherein Y1 is NR, O or S and R is H or an optional substituent as described hereinbelow. 
Similarly, as used in the specification and claims, the term heteroaryl designates a 5- to 10-membered monocyclic or bicyclic aromatic ring system containing 1 to 3 heteroatoms, which may be the same or different, selected from N, O or S. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl, thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl, indolinyl, benzothienyl, benzofuranyl, benzisoxazolyl and the like. The term haloalkyl designates a CnH2n+1 group having from one to 2n+1 halogen atoms which may be the same or different; and the term haloalkoxy designates an OCnH2n+1 group having from one to 2n+1 halogen atoms which may be the same or different.
In the specification and claims, when the terms C1-C6alkyl, C2-C6alkenyl, C2-C6alkynl, C3-C7cycloalkyl, cycloheteroalkyl, C1-C6alkanoyl, aryl or heteroaryl are designated as being optionally substituted, the substituent groups which are optionally present may be one or more of those customarily employed in the development of pharmaceutical compounds or the modification of such compounds to influence their structure/activity, persistence, absorption, stability or other beneficial property. Specific examples of such substituents include halogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl, haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl, alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl, alkylsulphonyl, carbamoyl, alkylamido, phenyl, phenoxy, benzyl, benzyloxy, cycloheteroalkyl, heteroaryl or cycloalkyl groups, preferably halogen atoms or lower alkyl groups. Typically, up to 3 substituents may be present. When any of the foregoing substituents represents or contains an alkyl substituent group, this may be linear or branched and may contain up to 12, preferably up to 6, more preferably up to 4 carbon atoms.
Pharmaceutically acceptable salts may be any acid addition salt formed by a compound of formula I and a pharmaceutically acceptable acid such as phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, mandelic, malonic, succinic, fumaric, acetic, lactic, nitric, sulfonic, p-toluene sulfonic, methane sulfonic acid or the like.
Compounds of the invention include esters, carbamates or other conventional prodrug forms, which in general, are functional derivatives of the compounds of the invention and which are readily converted to the inventive active moiety in vivo. Correspondingly, the method of the invention embraces the treatment of the various conditions described hereinabove with a compound of formula I or with a compound which is not specifically disclosed but which, upon administration, converts to a compound of formula I in vivo. Also included are metabolites of the compounds of the present invention defined as active species produced upon introduction of these compounds into a biological system.
Compounds of the invention may exist as one or more stereoisomers. The various stereoisomers include enantiomers, diastereomers, atropisomers and geometric isomers. One skilled in the art will appreciate that one stereoisomer may be more active or may exhibit beneficial effects when enriched relative to the other stereoisomer(s) or when separated from the other stereoisomer(s). Additionally, the skilled artisan knows how to separate, enrich or selectively prepare said stereoisomers. Accordingly, the present invention comprises compounds of Formula I, the stereoisomers thereof and the pharmaceutically acceptable salts thereof. The compounds of the invention may be present as a mixture of stereoisomers, individual stereoisomers, or as an optically active form.
Preferred compounds of the invention are those compounds of formula I wherein n is 1 and Y is NR8. Also preferred are those compounds of formula I wherein n is 0. Further preferred compounds of the invention are those compounds of formula I wherein Q is SO2 or CO and R5 is an optionally substituted aryl or heteroaryl group. Another group of preferred compounds is those compounds of formula I wherein ---- represents a single bond.
More preferred compounds of the invention are those compounds of formula I wherein n is 0; Q is SO2; X is CR7; and Z is NR11. Another group of more preferred inventive compounds are those formula I compounds wherein n is 1; Q is SO2; Y is NR8; X is CR7; and R5 is an optionally substituted aryl group. Further more preferred compounds of the invention are those compounds of formula I wherein n is 0; Q is So2; W is CR6; X is CR7; Z is NR11; R5 is an optionally substituted aryl group; and ---- represents a single bond.
Among the preferred compounds of the invention are:
1-(phenylsulfonyl)-3-(piperidin-4-yl)-1H-indazole;
1-(4-nitrophenyl)-3-(piperidin-4-yl)-1H-indazole;
1-(4-fluorophenyl)-3-(piperidin-4-yl)-1H-indazole;
1-(3,4-dimethoxyphenyl-3-(piperidin-4-yl)-1H-indazole;
1-(4-fluorophenylsulfonyl)-3-(1-methyl-pyrrolidin-3-yl)-1H-indole;
1-(4-chlorophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;
1-(naphth-2-ylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;
1-(4-aminophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;
1-(3,4-dimethoxyphenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;
1-(3,4-dichlorophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;
1-[(4,5-dichlorothien-2-yl)sulfonyl]-3-(1-methyl-pyrrolidin-3-yl)-1H-indole;
1-(2-bromophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;
1-(4-iodophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;
1-(2-iodophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indole;
1-(4-aminophenylsulfonyl)-3-(1-benzylpyrrolidin-3-yl)-1H-indole;
3-(1-benzylpyrrolidin-3-yl)-1-(4-methylphenylsulfonyl)-1H-indole;
3-(1-benzylpyrrolidin-3-yl)-1-(3,4-dichlorophenyl-sulfonyl)-1H-indole;
3-(1-benzylpyrrolidin-3-yl)-1-(2-bromophenylsulfonyl)-1H-indole;
5-[3-(1-benzylpyrrolidin-3-yl)-indole-1-sulfonyl]-4-methyl-thiazol-2-ylamine;
3-(1-benzylpyrrolidin-3-yl)-1-[(5-bromothien-2-yl)sulfonyl]-1H-indole;
1-phenylsulfonyl-3-(1-methylpyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine;
1-phenylsulfonyl-3-(1-methylpyrrolidin-3-yl)-1H-indazole;
1-phenylsulfonyl-3-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
1-phenylsulfonyl-3-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-indole;
1-phenylsulfonyl-3-(1-methylpiperidin-4-yl)-1H-indazole;
1-phenylsulfonyl-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indazole;
1-phenylsulfonyl-3-(1-methylazepan-4-yl)-1H-pyrrolo[2,3-b]pyridine;
1-phenylsulfonyl-3-(1-methylazepan-4-yl)-1H-indole;
1-phenylsulfonyl-5-fluoro-3-(1-methylazepan-4-yl)-1H-indole;
1-phenylsulfonyl-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;
1-phenylsulfonyl-3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;
1-phenylsulfonyl-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-pyrrolo[2,3-b]pyridine;
1-phenylsulfonyl-5-fluoro-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;
1-phenylsulfonyl-5-fluoro-3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1H-indole;
1-(benzo[b]thioen-4-ylsulfonyl)-3-(1-methyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine;
1-(3-fluorophenylsulfonyl)-3-(1-methylpyrrolidin-3-yl)-1H-indazole;
1-(2,5-dichlorophenylsulfonyl)-3-(2,5-dihydro-1H-pyrrol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
8-[3-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)indole-1-sulfonyl]-quinoline;
1-phenylsulfonyl-5-chloro-3-(1-methylpiperidin-4-yl)-1H-indazole;
5-methoxy-3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1-(naphth-1-yl-sulfonyl)-1H-indazole;
3-(1-methylazepan-4-yl)-1-(naphth-1-yl-sulfonyl)-1H-pyrrolo[2,3-b]pyridine;
3-(1-methylazepan-4-yl)-1-(naphth-1-yl-sulfonyl)-1H-indole;
1-(benzo[b]thien-4-ylsulfonyl)-5-fluoro-3-(1-methylazepan-4-yl)-1H-indole;
8-[3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-indole-1-sulfonyl]-quinoline;
3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1-(naphth-1-ylsulfonyl)-1H-indole;
8-[3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-pyrrolo[2,3-b]pyridine-1-sulfonyl]-quinoline;
8-[5-fluoro-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-indole-1-sulfonyl]-quinoline;
5-fluoro-3-(1-methyl-2,5,6,7-tetrahydro-1H-azepin-4-yl)-1-(naphth-1-ylsulfonyl)-1H-indole;
1-(benzo[b]thien-4-ylsulfonyl)-3-(1-benzyl-pyrrolidin-3-yl)-1H-pyrrolo[2,3-b]pyridine;
1-(3-fluoro-phenylsulfonyl)-3-(1-phenethyl-pyrrolidin-3-yl)-1H-indazole;
1-(2,5-dichlorophenylsulfonyl)-3-(1-ethyl-2,5-dihydro-1H-pyrrol-3-yl)-1H-pyrrolo[2,3-b]pyridine;
3-(1-methyl-2,5-dihydro-1H-pyrrol-3-yl)-1-(naphth-2-ylsulfonyl)-1H-indole;
5-chloro-1-(3-fluorophenylsulfonyl)-3-piperidin-4-yl-1H-indazole;
5-methoxy-1-(naphth-1-ylsulfonyl)-3-(1,2,2-trimethyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indazole;
1-(naphth-1-ylsulfonyl)-3-(1-phenethyl-azepan-4-yl)-1H-pyrrolo[2,3-b]pyridine;
3-azepan-4-yl-1-(naphth-1-ylsulfonyl)-1H-indole;
3-azepan-4-yl-1-(3-chloro-5-methyl-benzo[b]thien-2-ylsulfonyl)-5-fluoro-1H-indole;
8-[3-(1-phenethyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-indole-1-sulfonyl]-quinoline;
3-[1-(3,3-dimethylbutyl)-2,5,6,7-tetrahydro-1H-azepin-4-yl]-1-(naphth-2-ylsulfonyl)-1H-indole;
1-(2,3-dichlorophenylsulfonyl)-3-(1-methyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-1H-pyrrolo[2,3-]pyridine;
1-[(3-chloro-5-methoxyphenylsulfonyl)]-3-(2,2-dimethyl-2,3,6,7-tetrahydro-1H-azepin-4-yl)-5-fluoro-1H-indole;
3-azepan-4-yl-5-fluoro-1-(naphth-2-ylsulfonyl)-1H-indole;
1-benzenesulfonyl-3-piperidin-3-yl-1H-indole;
1-(4-isopropyl-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;
1-(5-chloro-thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-indole;
1-(3-chloro-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;
1-(3,4-difluoro-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;
1-(4-trifluoromethoxy-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;
1-(4-methoxy-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;
1-(4-trifluoromethy-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;
1-(3-chloro-4-methyl-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;
1-(2-chloro-4-trifluoromethyl-benzenesulfonyl)-3-piperidin-3-yl-1H-indole;
1-(2-naphthylenesulfonyl)-3-piperidin-3-yl-1H-indole;
1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-indole;
1-(2,6-dichloro-imidazo[2,1-b]thiazole-5-sulfonyl)-3-piperidin-3-yl-1H-indole;
2-chloro-3-(3-piperidin-3-yl-indole-1-sulfonyl)-imidazo[1,2-a]pyridine;
2-chloro-3-(3-piperidin-3-yl-indole-1-sulfonyl)-benzo[d]imidazo[2,1-b]thiazole;
1-(4-isopropyl-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
1-(5-chloro-thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
1-(3-chloro-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
1-(3,4-difluoro-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
1-(4-trifluoromethoxy-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
1-(3-chloro-4-methyl-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
1-(2-chloro-4-trifluoromethyl-benzenesulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
1-(2-naphthylenesulfonyl)-3- piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
1-(5-chloro-3-methyl-benzo[b]thiophene-2-sulfonyl)-3-piperidin-3-yl-1H-pyrrolo[2,3-b]pyridine;
2-chloro-3-(3-piperidin-3-yl-pyrrolo[2,3-b]pyridine-1-sulfonyl)-imidazo[1,2-a]pyridine;
2-chloro-3-(3-piperidin-3-yl-pyrrolo[2,3-b]pyridine-1-sulfonyl)-benzo[d]imidazo[2,1-b]thiazole;
or the pharmaceutically acceptable salts thereof.
Compounds of the invention may be prepared using conventional synthetic methods and, if required, standard separation or isolation techniques. For example, compounds of formula I wherein n is 1; Q is So2; Y is CH2; Z is NH; and ---- represents a double bond (Ia) may be prepared by reacting a compound of formula II with a protected 4-piperidone compound of formula III, such as 1-t-butoxycarbonyl-4-piperidone, in the presence of a base to give the protected tetrahydropyridinyl compound of formula IV; sulfonating said formula IV compound to give the protected 1-sulfonyl derivative of formula V; and deprotecting the formula V compound to give the desired formula Ia product. Alternatively, the formula V compound may be reduced to give the formula VI protected piperidin-4-yl derivative and deprotection of the formula VI compound affords the compound of formula I wherein n is 1; Q is SO2; Y is CH2, Z is NH; and ---- represents a single bond (1b). The reaction schemes are shown in flow diagram I wherein G represents a protecting group. 
Commonly used protecting groups include t-butylcarboxylate, benzyl, acetyl, benzyloxycarbonyl, or any conventional group known to protect a basic nitrogen in standard synthetic procedures.
The corresponding compounds of formula I wherein Z is NR11 and R11 is other than H may be prepared by alkylating the formula Ia or Ib compound with an alkylating agent R11-Hal, wherein Hal is Cl, Br or I. The reaction is illustrated in flow diagram II. 
Similarly, compounds of formula I wherein n is 1; Q is SO2; Y is NH and Z is CH2 (Id) may be prepared by reacting a formula II compound with a protected 3-piperidone of formula VII in the presence of a base to give the protected tetrahydropyridinyl compound of formula VIII; reducing said formula VIII compound via catalytic hydrogenation to give the compound of formula IX; sulfonating the formula VIII or IX compound to give the corresponding protected 1-sulfonyl derivative and deprotecting said derivative to give the desired product of formula Id. The reaction sequence is shown in flow diagram III wherein G represents a protecting group. 
Compounds of formula I wherein n is 0, Q is SO2; Y is CH2; Z is NH and ---- represents a single bond (Ie) may be prepared by reacting a compound of formula II with a protected maleimide in the presence of an acid to give the compound of formula X; reducing the formula X compound with LiAlH4 to give the 3-pyrrolidinyl compound of formula XI and sulfonating and deprotecting as described hereinabove to give the desired product of formula Ie. The reactions are shown in flow diagram IV wherein G represents a protecting group. 
Utilizing the reactions shown in flow diagrams I, II, and III hereinabove and employing the appropriate pyrrolidone or homopiperidone affords compounds of formula I wherein n is 0 or 2 and Q is SO2. Compounds of formula Id or Ie may be alkylated as shown in flow diagram III to give the corresponding formula I products wherein R8 or R11 is other than H. Compounds of formula I wherein Q is CO, CONR24 or CH2 may be prepared by reacting the protected intermediate of formula IV, VIII, IX or XI with the appropriate carbonyl halide, carbamoyl halide or alkyl halide, respectively. These and other literature procedures may be utilized to prepare the formula I compounds of the invention.
Advantageously, the inventive compound of formula I may be utilized in the treatment of central nervous system disorders relating to or affected by the 5-HT6 receptor such as motor, mood, psychiatric, cognitive, neurodegenerative, or the like disorders. In particular, CNS disorders such as anxiety, depression, schizophrenia, Alzheimer""s disease, Parkinson""s disease, eating disorders, disorders related to alcohol or drug withdrawl, sexual dysfunction, attention deficit, memory loss or the like. Accordingly, the present invention provides a method for the treatment of a disorder of the central nervous system (CNS) related to or affected by the 5-HT6 receptor in a patient in need thereof which comprises providing said patient with a therapeutically effective amount of a compound of formula I as described hereinabove. The compounds may be provided via oral or parenteral administration or in any common manner known to be an effective administration of a therapeutic agent to a patient in need thereof.
The therapeutically effective amount provided in the treatment of a specific CNS disorder may vary according to the specific condition(s) being treated, the size, age and response pattern of the patient, the severity of the disorder, the judgment of the attending physician and the like. In general, effective amounts for daily oral administration may be about 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg and effective amounts for parenteral administration may be about 0.1 to 100 mg/kg, preferably about 0.5 to 50 mg/kg.
In actual practice, the compounds of the invention are administered in a solid or liquid form, either neat or in combination with one or more conventional pharmaceutical carriers or excipients. Accordingly, the present invention provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and an effective amount of a compound of formula I as described hereinabove.
Solid carriers suitable for use in the composition of the invention include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aides, binders, tablet-disintegrating agents or encapsulating materials. In powders, the carrier may be a finely divided solid which is in admixture with a finely divided compound of formula I. In tablets, the formula I compound may be mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. Said powders and tablets may contain up to 99% by weight of the formula I compound. Solid carriers suitable for use in the composition of the invention include calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Any pharmaceutically acceptable liquid carrier suitable for preparing solutions, suspensions, emulsions, syrups and elixirs may be employed in the composition of the invention. Compounds of formula I may be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, or a pharmaceutically acceptable oil or fat, or a mixture thereof. Said liquid composition may contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers, osmo-regulators, or the like. Examples of liquid carriers suitable for oral and parenteral administration include water (particularly containing additives as above, e.g., cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g., glycols) or their derivatives, or oils (e.g., fractionated coconut oil and arachis oil). For parenteral administration the carrier may also be an oily ester such as ethyl oleate or isopropyl myristate.
Compositions of the invention which are sterile solutions or suspensions are suitable for intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions may also be administered intravenously. Inventive compositions suitable for oral administration may be in either liquid or solid composition form.
For a more clear understanding, and in order to illustrate the invention more clearly, specific examples thereof are set forth hereinbelow. The following examples are merely illustrative and are not to be understood as limiting the scope and underlying principles of the invention in any way.
Unless otherwise stated, all parts are parts by weight. The terms HPLC and NMR designate high performance liquid chromatography and nuclear magnetic resonance, respectively.